Transition metal-free cross-dehydrogenative arylation of unactivated benzylic C-H bonds

Article abstract of DOI:10.1039/d0cc06212j

The cross-dehydrogenative arylation of benzylic C-H bonds with arenes provides straightforward access to synthetically useful 1,1-diarylmethanes, from readily available starting materials. Current approaches suffer from limited substrate scope, requirement for large excesses of alkyl arene and/or non-trivial reaction set up. We report a transition metal-free cross-dehydrogenative arylation of benzylic C-H bonds using alkyl benzene derivatives and electron-rich arenes as coupling partners. The method proceeds through the in situ generation of a reactive benzyl fluoride intermediate which then reacts with the nucleophilic arene. The reaction tolerates a wide variety of functional groups including unprotected polar functionality and has been applied to the late-stage benzylation of several biologically relevant molecules.

Full text of DOI:10.1039/d0cc06212j

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DOI: 10.1039/D0CC06212J
ARTICLE
Transition Metal-free Cross-Dehydrogenative Arylation of
Unactivated Benzylic C–H Bonds
Andrew R. A. Spencer, Rachel Grainger, Adyasha Panigrahi, Thomas J. Lepper, Katarzyna
Bentkowska and Igor Larrosa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The cross-dehydrogenative arylation of benzylic C–H bonds with arenes provides straightforward access to synthetically
useful 1,1-diarylmethanes, from readily available starting materials. Current approaches suffer from limited substrate scope,
requirement for large excesses of alkyl arene and/or non-trivial reaction set up. We report a transition metal-free cross-
dehydrogenative arylation of benzylic C–H bonds using alkyl benzene derivatives and electron-rich arenes as coupling
partners. The method proceeds through the in situ generation of a reactive benzyl fluoride intermediate which then reacts
with the nucleophilic arene. The reaction tolerates a wide variety of functional groups including unprotected polar
functionality and has been applied to the late-stage benzylation of several biologically relevant molecules.
In recent years, direct C–C bond formation from inert C–H
bonds has emerged as an attractive synthetic strategy that
avoids pre-functionalisation of one or both starting materials,
leading to more step-economical and environmentally benign
access to complex molecules.1 In particular, cross-
dehydrogenative coupling (CDC) reactions involve the coupling
of two inert C–H bonds under oxidative conditions, eliminating
the requirement for pre-functionalisation of either precursor.2
Using this CDC approach, ‘activated’ intermediates are
generated in situ, often in a catalytic manner, thus streamlining
the synthesis of the target molecule.
Me
Cl
Cl
O
N
Me
O
NHMe
OH
Me2N
Me
Diphenylhydramine
antihistamine
Clemastine
antihistamine
Sertraline
antidepressant
MeO
O
Me
OH
O
O
iPr
N
N
OH
iPr
CDP-840
PDE-IV Inhibitor
Fesoteridine
antimuscarinic
Phenylethyl resorcinol
skin care product
Figure 1 Common pharmaceuticals containing the 1,1-diarylmethane motif.
Direct benzylic C–H arylation represents an attractive
approach for the direct formation of unsymmetrical 1,1-
diarylmethanes, a motif commonly found in pharmaceuticals
and other industrially relevant molecules (Figure 1).3
Furthermore, alkyl benzenes are inexpensive chemical
feedstocks and therefore are ideal synthetic starting materials
for elaboration to more valuable motifs.4 To date, a number of
strategies have been realised for the cross-dehydrogenative
arylation of benzylic C–H bonds (Scheme 1):5 a) Deprotonation
of the benzylic position leads to a benzylic carbanion, which can
then carry out a nucleophilic attack onto para-nitroarenes.6 This
method is, however, limited to benzylic positions bearing an
additional α-electron-withdrawing groups and to para-
nitroarene coupling partners. b) Hydrogen atom abstraction to
form a benzylic radical, which can then react with an arene.
However, a large excess of alkyl arene or activated benzylic
positions are often required.7 c) Oxidation of the benzylic
position to form a benzylic carbocation, which can in turn react
with a nucleophilic arene.
In general, this approach requires an activating group α to the
benzylic position, such as a heteroatom or an arene.8
Electrochemical oxidation of the benzylic position can also lead
to the corresponding benzylic carbocation, avoiding the need
for α-activating groups.9 However, this approach requires the
alkylbenzene to be para-substituted with an electron-donating
group and/or forcing conditions and a large excess of the
nucleophile are often needed.
We hypothesised that a fourth CDC route may become
available through the in situ formation of a benzylic electrophile
bearing a suitable leaving group. This activated intermediate
could then readily couple with a nucleophilic arene via a SEAr-
type pathway (Scheme 1d). We envisaged that such an
approach may result in a nucleophilic arene scope equivalent to
that observed in the cationic pathway but avoiding the need for
the presence of an α-activating group and/or a para electron-
donating group, thus providing a complementary substrate
scope to that currently available. The choice of ‘leaving group’
would be crucial to both allow its installation and its subsequent
reaction under mild conditions, while avoiding potential
polymerisation or elimination side reactions.
a. Department of Chemistry, School of Natural Sciences, University of Manchester,
Oxford Road, Manchester M13 9PL, United Kingdom.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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Sesamol and Resorcinol forming only one regioisomer of the
product (3ea, 3fa). Notably, no benzylation was observed at the
View Article Online
DOI: 10.1039/D0CC06212J
Base
EWG
p-NO2Ar
a)
R1
R2 = EWG
phenolic OH in any case. Simple arenes bearing no strong
electron donating groups were less reactive, with benzene
giving no conversion and p-xylene offering a modest 19%
conversion, both with 10 equivalents of arene. A variety of
nucleophilic heterocycles were also compatible with the
reaction conditions. Benzothiophenes were reactive at both C2
and C3 (3ha, 3ia). Pleasingly, several unprotected indoles were
also compatible with the reaction, in each case leading to
selective benzylation at the most nucleophilic C3-position.
Strong electron withdrawing groups could be tolerated on the
indole ring including methyl ester (3ja), a free carboxylic acid
(3ka) and nitro groups (3la). However, when more electron-rich
indoles were tested, complicated regioisomeric benzylation
mixtures were observed.
We then examined the scope of the alkyl arene coupling
partner using 2,4-dimethoxytoluene (2a) as the model arene
(Scheme 4). We started by varying the substitution and
electronics of the arene component. p-Ph proceeded in
excellent yield and reduced reaction time for the fluorination
reaction (3ac). Weakly and moderately electron withdrawing
groups such as p-F and p-OAc were also compatible giving
moderate to good yields of the product (3ad, 3ae). Stronger
electron withdrawing groups such as a free carboxylic acid were
not tolerated possibly due to the greater instability of the
corresponding benzylic carbocation (3an). However, when a
similarly strong electron withdrawing methyl ketone group was
placed in the meta position, the reaction proceeded albeit,
surprisingly, with the formation of around 12% of the
ortho,ortho-benzylated regioisomer (3ag). Placing a Cl in the
ortho position of the arene also led to around a 6:1 ratio of
benzylation isomers (3af). Next, the R2 substituent adjacent to
Ar
H
Radical
initiator
b)
ArH
ArH
2
R2
R2
R2
R1
R1
R1
1 as solvent
or R2 = O, N, Ar
3
1
c)
R2
[Ox]
2
nucleophile
R1
R1 = p-OMe or R2 = O, N, Ar
d)
28 Examples
Broad substrate
scope
Alkyl arene-limited
Late-stage
functionalisation
LG
R2
This work
ArH
nucleophile
"LG X"
2
R1
Scheme 1- Current approaches for cross-dehydrogenative benzylic arylation
We reasoned that benzylic fluorides may be ideal activated
intermediates for our strategy. A plethora of methods for
benzylic C–H fluorination have been reported.10 Furthermore,
Paquin, Stephan and others have shown that benzyl mono
fluorides can be activated to nucleophilic attack by both Lewis
acids and by hydrogen bonding interactions.11 Neat benzylic
fluorides are often unstable and prone to polymerisation,
making them ideal intermediates in a one-pot process where
isolation of the intermediate is avoided.12 Herein, we report
success on this strategy, affording a method tolerant of a wide
range of functional groups and compatible with the late-stage
diversification of bioactive molecules, using only a fluorinating
agent as the stoichiometric oxidant in the absence of any
transition metal catalysts.13
We began our studies by testing Chen’s benzylic fluorination
of 1a using 9-fluorenone as photocatalyst, Selectfluor and
visible light,10c as a protocol for accessing the benzylic fluoride
intermediate (Scheme 2). Indeed, to our delight, we found that
simple addition of the nucleophilic arene 2,4-dimethoxytoluene
(2a) after 24 h, followed by heating to 90 °C for 30 min, led to
the desired product (3aa) in a 72% yield as a single regioisomer.
with substitution occurring at the most electron rich and less
hindered position on the arene ring. Notably, the use of HFIP11c
or of [(C6F5)3PF][B(C6F5)4] and Et3SiH11g were not required for
the arylation step to proceed.
the benzylic position was varied. Extension of the alkyl chain
i) Selectfluor (2.0 equiv) , 9-
fluorenone (5 mol %), 18 W
CFL, RT, 24 h, MeCN
H
Ar(Het)
tBu
tBu
Me
Me
(Het)Ar
2
H
ii) 2 (2.0 equiv), 90 °C, 30 min,
MeCN
3
1, 0.4 mmol
OMe
OH
Me
MeO
Me
Me
*
With the optimised conditions in hand, we examined the
scope of the reaction with respect to the nucleophilic arene,
using 1-(tBu)-3-ethylbenzene (1a) as the model alkylarene
(Scheme 3). Anisoles reacted well, giving preference for para-
benzylation over the ortho position (3aa). However, if the para
position is blocked then reactivity can be observed at ortho,
albeit under more forcing conditions (3ba, 3ca). A variety of
phenols were also observed to benzylate under these
conditions. o-Cresol showed preferential para-benzylation, with
a small amount of ortho-product being observed (3da).
Naturally occurring phenols such as Resorcinol, Sesamol and
Eugenol all performed well in the reaction (3ea, 3fa, 3ga), with
OMe
OMe
tBu
OMe
tBu
tBu
tBu
tBu
tBu
Me
Me
Me
3ca, 48%c
Me
3ba, 40%c
3da, 57% (*12%a)c
3aa, 72%
OH
O
OMe
O
HO
S
Me
*
OH
tBu
HO
tBu
tBu
Me
Me
Me
Me
3ga, 54% (*18%a)
3ea, 60%
3fa, 69%
3ha, 65%
CO2Me
CO2H
NO2
HN
HN
HN
S
Me
Me
OMe
tBu
i) Selectfluor (2.0 equiv),
9-fluorenone (5 mol %),
18 W CFL, RT, 24 h, MeCN
tBu
tBu
H
OMe
Me
Me
Me
Me
Me
tBu
Me
1a, 0.4 mmol
tBu
3ka, 55%b
ii) 2a (2.0 equiv), 90 °C,
3ja, 52%
OMe
2a
3ia, 45%
3la, 61%
30 min, MeCN
3aa, 72%
Me
OMe
All yields are of pure isolated compounds a Yield determined by 1H NMR using CH2Br2 as an internal
H
standard. b 3 equiv of 2 used in step ii. c 4 equiv of 2 used in step ii.
Scheme 2- Initial discovery of the cross-dehydrogenative benzylic arylation
Scheme 3-Scope in nucleophilic arene
2 | J. Name., 2012, 00, 1-3
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ARTICLE
from an ethyl to a propyl group led to no significant drop in selectively in a good yield (3ma). HexylresorcinolViisewaArptihcleenOnolilnice
DOI: 10.1039/D0CC06212J
yield (3ah). Placing another phenyl group adjacent to the compound that is used as a local anesthetic and can be
benzylic position should stabilise both the radical and benzylated regioselectively in moderate yield (3na).
carbocation intermediates and indeed it showed excellent Homoveratic acid (1o) is a dimethylated metabolite of L-DOPA
reactivity (3ai). Protected alcohols and amines were both which was selectively para-benzylated (3oa). Moderate yield in
compatible with the procedure giving good yields with slightly this case results from a competitive O-benzylation side product
elevated reaction times for the fluorination (3aj, 3ak). This deriving from nucleophilic attack of the carboxylic acid into the
method can also be used for the rapid construction of benzyl fluoride. Oxybenzone is a UV-absorbent and a common
quaternary carbon centers by starting from the corresponding additive in sun creams. Benzylation occurred preferentially para
isopropylbenzene. In this case longer reaction times and more to the phenolic MeO group, with a small amount of ortho
equivalents of nucleophilic arene are required to facilitate the substituted product (3pa). Notably, oxybenzone can be
addition into a more sterically hindered electrophile (3al). benzylated in good yield despite bearing an aryl ketone
Finally, despite giving excellent yields in the fluorination step, electron-withdrawing group. Finally, gemfibrozil is a lipid lowing
toluene derivatives were incompatible with the method (3ao), drug of the fibrate class used to treat high levels of cholesterol.
likely due to the less favorable formation of a primary benzylic As expected, benzylation occurred para to the aryl ether in a
carbocation. This is in contrast with the arylations of benzyl good yield. Remarkably, in this case the protocol was
fluorides by Paquin and Stephan,11c,11g where toluene compatible with the free carboxylic acid in gemfibrozil with no
derivatives are the most reactive electrophiles, and only O-benzylation observed (3qa).
H
Ar
i) Selectfluor (2.0 equiv) , 9-
fluorenone (5 mol %), 18 W
CFL, RT, 3 h, MeCN
electron-deficient secondary benzylic fluorides are found to
undergo arylation. The cross-dehydrogenative benzylation of
3ac and 2a could be easily scaled up to 4 mmol, affording >1 g
of product 3ac, in 75% yield).
Me
0.4 mmol
Me
Ar
H
R1
R1
ii) 2 (2.0 equiv), 90 °C, 30 min,
1
2
3
MeCN
OMe
OH
tBu
MeO
We then further examined the synthetic utility of this
method in its application to the late stage benzylation of
biologically relevant molecules. Given that phenols are
extremely ubiquitous motifs amongst pharmaceuticals14 and
biologically relevant molecules, we reasoned that our method
could be particularly well suited to the late-stage
functionalisation of molecules of this class (Scheme 5). Estrone,
was subjected to the reaction conditions and was benzylated
n-Hex
O
O
Me
H
OH
OH
H
tBu
Me
Me
Me
H
HO
Ph
3ma, 64%b
3na, 31%c,d
From hexylresorcinol: Local
anasthetic
3oa, 28%b
From estrone: Female sex
From homoveratic acid: L-
DOPA metabollite
hormone
OMe
O
Me
*
Me
CO2H
OMe
O
HO
OMe
Me
i) Selectfluor (2.0 equiv) , 9-
H
Me
fluorenone (5 mol %), 18 W
CFL, RT, 24 h, MeCN
Me
Me
R2
OMe
R1
OMe
Ph
3pa, 36%(*17%a)
Ph
3qa, 67%
ii) 2 (2.0 equiv), 90 °C, 30 min,
R2
H
From gemfibrozil: Lipid lowering
From oxybenzone: UV absorbant
R1
MeCN
1, 0.4 mmol
2
3
All yields are of pure isolated compounds. a Yield determined by 1H NMR using CH2Br2 as an
OMe
OMe
OMe
Me
OMe
internal standard.b Step i run for 24 h. c 3 equiv of 2 used in step ii. d Step ii run for 3 h
Me
Me
Me
Scheme 5-Benzylation of biologically relevant molecules
OMe
Ph
OMe
OMe
OMe
We carried out preliminary mechanistic studies on the
arylation step (Scheme 6). Reaction of benzyl fluoride 4a and
electron rich arene 2a led to no formation of the coupling
product 3aa, with only recovered starting material observed.
However, when a catalytic amount of Selectfluor was added,
good conversion to 3aa was observed. Thus, Selectfluor seems
to play a key role in the activation of the benzyl fluoride
intermediate. While further mechanistic studies will need to be
performed to reveal its role, we speculate that Selectfluor may
be involved in the formation of small amounts of HF that could
then mediate the reaction through hydrogen bonding activation
as proposed by Paquin.11c We confirmed that under these
conditions, HF is able to catalyse the reaction, forming 3aa in a
46% yield.
Me
Me
Me
Me
F
*
AcO
3ab, 68%e
OMe
3ac, 80%f
3ad, 77%
3ae, 47%b,h,j
OMe
OMe
OMe
Me
Me
Me
Me
*
Cl
OMe
O
OMe
OMe
Me
OMe
Me
Me
Ph
3af, 47%(*7%a)d,i
3ag, 70%(*12%a)d,i
3ah, 50%e
OMe
3ai, 69%
OMe
OMe
OMe
Me
Me
Me
Me
OMe
OMe
NPhth
Ph
OMe
OMe
OAc
R2
Me
Me
R1
3aj, 61%e
3ak, 64%e
R1=OMe R2=Me 3am, 0%a
R1=CO2H R2=Me 3an, 0%a
R1=Ph R2=H 3ao, 0%a
3al, 45%d,g,i
In conclusion, we have developed a widely applicable
method for the cross-dehydrogenative arylation of benzylic C–
H bonds. The one-pot process proceeds through an initial
benzylic C–H fluorination to form a benzylic fluoride, which then
undergoes a Friedel-Crafts benzylation with a nucleophilic
All yields are of pure isolated compounds a Yield determined by 1H NMR using CH2Br2 as an internal
standard. b 3 equiv of 2 used in step ii. c 4 equiv of 2 used in step ii. d 5 equiv of 2 used in step ii. e
Step i run for 48 h. f Step i run for 3 h. g Step i run for 6 h. h Step ii run for 3 h. i Step ii run for 16 h. j
15 mol % 9-fluorenone used.
Scheme 4-Scope in ethyl benzene derivative
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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arene. A wide variety of functional groups are tolerated
including alkenes, halides and unprotected polar functionalities
(aromatic OH and NH, and free carboxylic acids), and the
method is compatible with a range of nucleophilic arenes and
heteroarenes. Importantly, the applicability of this reaction to
real-world molecules was demonstrated with examples of late-
stage benzylation of some biologically relevant compounds.
8
Me
OMe
OMe
F
Me
Additive
Me
90 °C, 30 min, MeCN
Additive
OMe
4a
2a
H
3aa
Me
OMe
None
Selectfluor (5 mol %)
HF (5 mol %)
No reaction
98%
46%
Scheme 6-Preliminary mechanistic studies
9
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We gratefully acknowledge the European Research Council for
an Advanced Grant (to I.L.), and Erasmus+ for a mobility
traineeship (to K.B.).
Notes and references
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